Mutant huntingtin protein induces MLH1 degradation, DNA hyperexcision, and cGAS-STING-dependent apoptosis.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The repeat-expanded HTT encodes a mutated HTT (mHTT), which is known to induce DNA double-strand breaks (DSBs), activation of the cGAS-STING pathway, and apoptosis in HD. However, the mechanism by which mHTT triggers these events is unknown. Here, we show that HTT interacts with both exonuclease 1 (Exo1) and MutLα (MLH1-PMS2), a negative regulator of Exo1. While the HTT-Exo1 interaction suppresses the Exo1-catalyzed DNA end resection during DSB repair, the HTT-MutLα interaction functions to stabilize MLH1. However, mHTT displays a significantly reduced interaction with Exo1 or MutLα, thereby losing the ability to regulate Exo1. Thus, cells expressing mHTT exhibit rapid MLH1 degradation and hyperactive DNA excision, which causes severe DNA damage and cytosolic DNA accumulation. This activates the cGAS-STING pathway to mediate apoptosis. Therefore, we have identified unique functions for both HTT and mHTT in modulating DNA repair and the cGAS-STING pathway-mediated apoptosis by interacting with MLH1. Our work elucidates the mechanism by which mHTT causes HD.

Opting for conservative management over surgery for neonatal ovarian cysts.

OBJECTIVE: To explore the suitability of conservative management for neonatal ovarian cysts in newborns. METHODS: A retrospective cohort study was conducted, involving infants diagnosed with neonatal abdominal/pelvic cysts at two separate medical institutions from January 2015 through July 2021. Data collection included clinical characteristics, imaging results, pathological findings, and postnatal outcomes. Statistical analyses were performed using the Student's t-test, Mann-Whitney U-test, and receiver operating characteristic (ROC) curve. RESULTS: In total, 34 cases of neonatal abdominal/pelvic cystic masses were detected, with mean birth weight of 3401 ± 515 g. Of these, 22 patients underwent postnatal cystectomy/oophorectomy. Pathological assessments revealed 16 uncomplicated cysts, 5 complex cysts, and 1 ovarian cyst with torsion complications. Notably, the cysts' dimensions at the time of surgical intervention had significantly decreased from the initial measurements (p = 0.015). The ROC curve analysis presented an area under the curve of 0.642, indicating moderate accuracy in employing cyst size as a discriminative feature to differentiate complex from simple ovarian cysts. Additionally, a short-term follow-up of nonsurgical cases indicated a 100% resolution rate by 24 months of age (n = 9). CONCLUSION: Given their predominantly benign nature, the majority of neonatal ovarian cysts seem to be amenable to conservative management. This approach remains justified for larger cysts with minimal torsion risk, as well as considering the observed reduction in cyst size at birth, which further supports the case against surgical intervention.

[A clinical analysis of bacterial meningitis in full-term and preterm infants].

OBJECTIVE: To study the clinical features and prognosis of bacterial meningitis in full-term and preterm infants. METHODS: A retrospective analysis was performed for the clinical data of 102 neonates with bacterial meningitis. According to the gestational age, they were divided into a preterm group (n=46) and a full-term group (n=56). The two groups were compared in terms of clinical manifestations, laboratory markers, imaging findings, and clinical outcomes. RESULTS: Poor response and apnea were the major clinical manifestations in the preterm group (P<0.05), while pyrexia and convulsions were more common in the full-term group (P<0.05). The full-term group had a significantly higher glucose level in cerebrospinal fluid (CSF) than the preterm group (P<0.05). Compared with the full-term group, the preterm group had significantly higher C-reactive protein level, positive rate of blood culture, and incidence rate of poor prognosis (P<0.05). There were no significant differences between the two groups in leukocyte count in peripheral blood, levels of leukocytes and protein in CSF, and positive rate of CSF culture (P>0.05). CONCLUSIONS: There are certain differences in the clinical manifestations between full-term and preterm infants with bacterial meningitis. Preterm infants tend to have a higher incidence rate of poor prognosis.

[Efficacy of different preparations of budesonide combined with pulmonary surfactant in the treatment of neonatal respiratory distress syndrome: a comparative analysis].

OBJECTIVE: To study the efficacy of different preparations of budesonide combined with pulmonary surfactant (PS) in improving blood gas levels and preventing bronchopulmonary dysplasia (BPD) in preterm infants with neonatal respiratory distress syndrome (NRDS). METHODS: A total of 184 preterm infants who developed NRDS within 4 hours after birth were randomly administered with PS + continuous inhalation of budesonide aerosol (continuous aerosol group), PS+budesonide solution (solution group), PS + single inhalation of budesonide aerosol (single aerosol group), and PS alone, with 46 neonates in each group. The changes in arterial blood gas levels, rate of invasive mechanical ventilation after treatment, time of assisted ventilation, rate of repeated use of PS, and the incidence of BPD were compared between the four groups. RESULTS: On the 2nd to 4th day after treatment, pH, PCO2, and oxygenation index (FiO2/PaO2) showed significant differences among the four groups, and the continuous aerosol group showed the most improvements of all indicators, followed by the solution group, single aerosol group, and PS alone group. The continuous aerosol group had a significantly shorter time of assisted ventilation than the other three groups (P<0.05). The solution group had a significantly shorter time of assisted ventilation than the single aerosol and PS alone groups (P<0.05). The rate of invasive mechanical ventilation after treatment, rate of repeated use of PS, and incidence of BPD showed significant differences among the four groups (P<0.05), and the continuous aerosol group had the lowest rates, followed by the solution group. CONCLUSIONS: A combination of PS and continuous inhalation of budesonide aerosol has a better efficacy in the treatment of NRDS than a combination of PS and budesonide solution. The difference in reducing the incidence of BDP between the two administration methods awaits further investigation with a larger sample size.

[Relationship between genetic polymorphisms of IRF6 rs642961 and nonsysdromic cleft lip with or without cleft palate].

OBJECTIVE: To explore the relationship between polymorphism of interferon regulatory factor 6 (IRF6) gene rs642961 locus and nonsyndromic cleft lip with or without cleft palate (NSCL ± P). METHODS: There were 88 NSCL ± P nuclear families and 116 healthy people as control recruited from Chinese northern area. The polymorphism of IRF6 rs642961 locus was detected by tetra-primer amplification refractory mutation system-polymerase chain reaction (tetra-primer ARMS-PCR). Case-control analysis, transmission-disequilibrium test (TDT), haplotype-based haplotype relative risk analysis (HHRR) and family-based association test (FBAT) were carried out. RESULT: There was significant difference in rs642961 of IRF6 locus between the NSCL P group and control group, whether in children or parents (P < 0.05). The odds ratio (OR) of AG and AA versus GG is above one, and its 95% confidence interval did not include 1 in offspring, father and mother group, which meant genetic variant of rs642961 of IRF6 could increase the risk of occurrence of NSCL ± P. The allele transmission disequilibrium for rs642961 of IRF6 variant in NSCL ± P families was found by TDT analysis (P < 0.05). HHRR calculation also showed that there was association between the genetic variant and the occurrence of NSCL ± P (P < 0.05). While FBAT test showed that there was relationship between the genetic variant and the occurrence of NSCL ± P in addictive model. CONCLUSION: Polymorphism IRF6 gene locus is associated with NSCL ± P in northern Chinese population.

Coordinated processing of 3' slipped (CAG)n/(CTG)n hairpins by DNA polymerases ß and δ preferentially induces repeat expansions.

Expansion of CAG/CTG trinucleotide repeats causes certain familial neurological disorders. Hairpin formation in the nascent strand during DNA synthesis is considered a major path for CAG/CTG repeat expansion. However, the underlying mechanism is unclear. We show here that removal or retention of a nascent strand hairpin during DNA synthesis depends on hairpin structures and types of DNA polymerases. Polymerase (pol) δ alone removes the 3'-slipped hairpin using its 3'-5' proofreading activity when the hairpin contains no immediate 3' complementary sequences. However, in the presence of pol ß, pol δ preferentially facilitates hairpin retention regardless of hairpin structures. In this reaction, pol ß incorporates several nucleotides to the hairpin 3'-end, which serves as an effective primer for the continuous DNA synthesis by pol δ, thereby leading to hairpin retention and repeat expansion. These findings strongly suggest that coordinated processing of 3'-slipped (CAG)n/(CTG)n hairpins by polymerases δ and ß on during DNA synthesis induces CAG/CTG repeat expansions.

Association between interferon regulatory factor 6 gene polymorphisms and nonsyndromic cleft lip with or without cleft palate in a chinese population.

Objective : To further confirm the association between two IRF6 single nucleotide polymorphisms and nonsyndromic cleft lip with or without cleft palate in a Chinese population. Participants : A total of 106 nonsyndromic cleft lip with or without cleft palate case trios and 129 control trios. Intervention : Two IRF6 single nucleotide polymorphisms, rs2235371 and rs642961, were genotyped for all case and control families. Case-control analysis and family-based linkage analysis were both performed for the two single nucleotide polymorphisms. Results : The genotype and allele frequencies of rs2235371 (odds ratioAG+AA vs. GG, 0.581; 95% confidence interval, 0.345 to 0.976; P = .039) and rs642961 (odds ratioAG+AA vs. GG, 5.389; 95% confidence interval, 2.936 to 9.893; P = 5e-08) were significantly higher in nonsyndromic cleft lip with or without cleft palate patients compared with controls. There was an obvious dosage effect of allele A at rs642961. The transmission of a major allele (G) of rs2235371 and a minor allele (A) of rs642961 was in disequilibrium (P < .05) in complete case-parent trios. The association between the two single nucleotide polymorphisms and nonsyndromic cleft lip with or without cleft palate was confirmed by the Family-Based Association Test for rs642961 (P = .008), but there was no significance for rs2235371 (P = 0.057). Haplotype analysis found that rs2235371 G/rs642961 A haplotype increased the risk of nonsyndromic cleft lip with or without cleft palate (P = 2.42e-07); whereas, rs2235371 A/rs642961 G haplotype reduced the risk of nonsyndromic cleft lip with or without cleft palate (P = 4.37e-05). No evidence of linkage disequilibrium was found between the two single nucleotide polymorphisms (D' = 0.303, r(2) = 0.017). Conclusion : Our results confirmed the involvement of the IRF6 variants rs642961 and rs2235371 in the etiology of nonsyndromic cleft lip with or without cleft palate in a Chinese population.

The effect of prenatal stress on offspring depression susceptibility in relation to the gut microbiome and metabolome.

Prenatal stress (PS) increases offspring susceptibility to depression, but the underlying mechanism remains unclear. Our previous results showed that PS can affect depression-like behavior in offspring through neurotransmitters and neuroinflammatory substances in the hippocampus and frontal cortex. In recent years there has been increasing evidence for a role of the gut microbiome in depression. The brain-gut axis theory suggests there is a need to further explore the mechanism involving the gut microbiome in the susceptibility of offspring to depression caused by PS. In the present study we used a stress model relevant to depression in which pregnant female rats undergo prenatal restraint stress and the offspring show susceptibility to depression. High-resolution gene sequencing for 16S ribosomal RNA markers and non-targeted metabolomic analysis were used to evaluate the fecal microbiome and the availability of metabolites, respectively. PS was found to induce depressive-like behavior in susceptible offspring (PS-S), as detected by the sucrose preference and forced swimming tests, as well as altering Alpha and Beta diversity. The different microbiota between the PS-S and control groups were mainly involved in membrane transport, carbohydrate metabolism, amino acid metabolism, and replication and repair pathways. In total, 237 and 136 important differential metabolites with significant influence on modeling analysis were obtained under positive and negative modes, respectively. The main canonical pathways found to be altered were glycerophospholipid metabolism and glycerolipid metabolism. These results suggest that gut microbiota might contribute to the onset of PS-induced depression-like behavior by affecting the glycerophospholipid and glycerolipid metabolic pathways.

A longitudinal study of polygenic score and cognitive function decline considering baseline cognitive function, lifestyle behaviors, and diabetes among middle-aged and older US adults.

BACKGROUND: Genomic study of cognition decline while considering baseline cognition and lifestyle behaviors is scarce. We aimed to evaluate the impact of a polygenic score for general cognition on cognition decline rate, while considering baseline cognition and lifestyle behaviors, among the general population and people with diabetes, a patient group commonly affected by cognition impairment. METHODS: We tested associations of the polygenic score for general cognition with annual changing rates of cognition measures in 8 years of follow-up among 12,090 White and 3100 Black participants of the Health and Retirement Study (HRS), a nationally representative sample of adults aged 50 years and older in the USA. Cognition measures including word recall, mental status, and total cognitive score were measured biannually. To maximize sample size and length of follow-up, we treated the 2010 wave of survey as baseline, and follow-up data until 2018 were analyzed. Baseline lifestyle behaviors, APOE status, and measured cognition were sequentially adjusted. Given racial differences in polygenic score, all analyses were conducted by race. RESULTS: The polygenic score was significantly associated with annual changing rates of all cognition measures independent of lifestyle behaviors and APOE status. Together with age and sex, the polygenic score explained 29.9%, 15.9%, and 26.5% variances of annual changing rates of word recall, mental status, and total cognitive scores among Whites and explained 17.2%, 13.9%, and 18.7% variance of the three traits among Blacks. Among both White and Black participants, those in the top quartile of polygenic score had the three cognition measures increased annually, while those in the bottom quartile had the three cognition measures decreased annually. After further adjusting for the average cognition assessed in 3 visits around baseline, the polygenic score was still positively associated with annual changing rates of all cognition measures for White (P ≤ 2.89E - 19) but not for Black (P ≥ 0.07) participants. In addition, among participants with diabetes, physical activity offset the genetic susceptibility to decline of mental status (interaction P ≤ 0.01) and total cognitive scores (interaction P = 0.03). CONCLUSIONS: Polygenic score predicted cognition changes in addition to measured cognition. Physical activity offset genetic risk for cognition decline among diabetes patients.

[Association between polymorphism of IRF6 rs2235371 locus and nonsyndromic cleft lip with or without cleft palate].

OBJECTIVE: To assess the association between polymorphism of interferon regulatory factor 6 (IRF6) gene rs2235371 locus and nonsyndromic cleft lip with or without cleft palate in Chinese population. METHODS: Blood samples from 106 patients and their parents and 129 controls and their parents were collected. The polymorphism of IRF6 rs2235371 locus was determined with PCR-restriction fragment length polymorphism (PCR-RFLP) method. Case-control analysis, transmission disequilibrium test(TDT), haplotype-based haplotype relative risk analysis (HHRR) and family-based association test (FBAT) were carried out. RESULTS: By case-control analysis, no significant difference was found in the frequencies of GG, GA and AA genotypes of rs2235371 locus between the patient group and control group (P> 0.05), but there was a significant difference in allelic frequencies (P< 0.05). There was also a significant difference in genotype and gene frequencies of rs2235371 variant between family members from cleft lip only group and control group. However, in cleft lip with cleft palate group, no such difference was observed. TDT analysis suggested a linkage in the presence of disequilibrium (chi-square=5.56, P=0.024). Results of HHRR analysis (chi-square=5.115, P=0.024) and FBAT (Z=2.218, P=0.027) also indicated an association between IRF6 rs2235371 variant and the risk of NSCL with or without cleft palate. CONCLUSION: Genetic polymorphism of IRF6 gene rs2235371 locus is associated with NSCL with or without cleft palate.

The Association of Human Milk Feeding With Short-Term Health Outcomes Among Chinese Very/Extremely Low Birth Weight Infants.

BACKGROUND: There is limited evidence about the influence of human milk feeding on short-term outcomes in a large preterm infant population. RESEARCH AIMS: To explore the influences of human milk feeding on the primary outcome of necrotizing enterocolitis and secondarily sepsis, bronchial pulmonary dysplasia, severe retinopathy of prematurity, death, and the time to achieve full enteral feeding at discharge in very/extremely low-birth-weight infants. METHODS: This study was a retrospective, longitudinal, observational two-group comparison cohort study. A total of 4470 very/extremely low-birth-weight infants from 25 neonatal intensive care units in China, between April 2015 and May 2018, were enrolled in this study. Exclusive human milk-fed and formula-fed participants were matched using propensity scores. After matching, human milk-fed participants (n = 1379) and formula-fed participants (n = 1378) were included in the analyses. The likelihood of necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, severe retinopathy of prematurity, death, and the time to achieve full enteral feeding were compared between the two groups. RESULTS: Exclusive human milk feeding was associated with lower odds of necrotizing enterocolitis (2.90% vs. 8.42%, OR 0.33, 95% CI [0.22, 0.47]), bronchopulmonary dysplasia (15.74% vs. 20.26%, OR 0.69, 95% CI [0.56, 0.86]), severe retinopathy of prematurity (1.45% vs. 2.39%, OR 0.50, 95% CI [0.27, 0.93]), and death (6.02% vs. 10.38%, OR 0.44, 95% CI [0.32, 0.61]) compared with formula feeding. No significant differences in the time to achieve full enteral feeding or the odds of sepsis were found between the two groups. CONCLUSION: Exclusive human milk feeding is associated with a reduction in necrotizing enterocolitis, bronchopulmonary dysplasia, severe retinopathy of prematurity, and mortality among very/extremely low-birth-weight infants. TRIAL REGISTRATION: Clinicaltrials.gov on November 9, 2015 (NCT02600195).

The Utility of Peripheral Blood Leucocyte Ratios as Biomarkers in Neonatal Sepsis: A Systematic Review and Meta-Analysis.

Background: Early stage diagnosis of neonatal sepsis (NS) remains a major roadblock due to non-specific symptoms and the absence of precise laboratory index tests. The full blood count is a relatively cheap, universal, and rapid diagnostic test. Method: This study assessed the diagnostic accuracies of immature-to-total neutrophil ratio (ITR), immature-to-mature neutrophil ratio (IMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) used in the diagnosis of NS. Included studies were retrieved by searching four major databases and relevant references, and reviewed based on the inclusion/exclusion criteria. Pooled sensitivities and specificities were calculated, I 2 was utilized to test for heterogeneity, and the source was investigated via meta-regression analysis. Results: Finally, 38 studies passed the eligibility criteria. A total of thirty-one studies (6,221 neonates) included data on the ITR, eight studies (1,230 neonates) included data on the IMR, seven studies (751 neonates) included data on the NLR, and two studies (283 neonates) included data on the PLR. The summary sensitivity estimates with 95% confidence interval (CI) for the ITR, IMR, NLR, and PLR tests were, respectively, 0.74 (95% CI: 0.66-0.80), 0.74 (95% CI: 0.54-0.88), 0.73 (95% CI: 0.68-0.78), and 0.81 (95% CI: 0.55-1.00). The summary specificity values for the ITR, IMR, NLR, and PLR tests were 0.83 (95% CI: 0.77-0.87), 0.89 (95% CI: 0.80-0.94), 0.69 (95% CI: 0.57-0.79), and 0.93 (95% CI: 0.81-1.00), respectively. The area under the summary receiver operating characteristic curves for the ITR, IMR, and NLR tests were 0.85 (95% CI: 0.82-0.88), 0.91 (95% CI: 0.88-0.93), and 0.75 (95% CI: 0.71-0.79). The PLR could not be evaluated because only two studies included pertinent data. Conclusion: The NLR test might not be sufficiently accurate in precisely diagnosing NS. The ITR and IMR tests alone can improve the accuracy of NS diagnosis, but the marked heterogeneity and the limited number of studies prevented us from reaching any definitive conclusions. Thus, further studies are warranted to validate these findings. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021247850].

Novel pathogenic variant (c.2947C > T) of the carbamoyl phosphate synthetase 1 gene in neonatal-onset deficiency.

Background: Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder characterized by hyperammonaemia. The biochemical measurement of the intermediate metabolites is helpful for CPS1D diagnosis; it however cannot distinguish CPS1D from N-acetylglutamate synthetase deficiency. Therefore, next-generation sequencing (NGS) is often essential for the accurate diagnosis of CPS1D. Methods: NGS was performed to identify candidate gene variants of CPS1D in a Asian neonatal patient presented with poor feeding, reduced activity, tachypnea, lethargy, and convulsions. The potential pathogenicity of the identified variants was predicted by various types of bioinformatical analyses, including evolution conservation, domain and 3D structure simulations. Results: Compound heterozygosity of CPS1D were identified. One was in exon 24 with a novel heterozygous missense variant c.2947C > T (p.P983S), and another was previously reported in exon 20 with c.2548C > T (p.R850C). Both variants were predicted to be deleterious. Conservation analysis and structural modeling showed that the two substituted amino acids were highly evolutionarily conserved, resulting in potential decreases of the binding pocket stability and the partial loss of enzyme activity. Conclusion: In this study, two pathogenic missense variants were identified with NGS, expanding the variants pectrum of the CPS1 gene. The variants and related structural knowledge of CPS enzyme demonstrate the applicability for the accurate diagnosis of CPS1D.

Terminal 10q26.12 deletion is associated with neonatal asymmetric crying facies syndrome: a case report and literature review.

BACKGROUND: The terminal 10q26 deletion syndrome is a clinically heterogeneous disorder without identified genotype-phenotype correlations. We reported a case of congenital asymmetric crying facies (ACF) syndrome with 10q26.12qter deletion and discussed their genotype-phenotype correlations and the potentially contributing genes involving the etiology of ACF. METHODS AND RESULTS: We reported a case of neonatal 10q26.12qter deletion and summarized the genotype-phenotype correlations and contributing genes of 10q26.12qter deletion from DECIPHER database and published studies. Meanwhile, we analyzed the potential pathogenic genes contributing to 10q26 deletion syndrome. The female preterm infant harboring 10q26.12qter deletion showed symptoms of abnormal craniofacial appearance with rare congenital asymmetric crying facies, developmental retardation, congenital heart disease, and pulmonary artery hypertension. The deleted region was 13.28 Mb in size as detected by G-banding and array comparative genome hybridization, containing 62 Online Mendelian Inheritance in Man (OMIM) catalog genes. We summarized data from 17 other patients with 10q26.12qter deletion, 11 from the DECIPHER database and 6 from published studies. Patients with monoallelic WDR11 and FGFR2 deletions located in 10q26.12q26.2 were predisposed to craniofacial dysmorphisms, growth retardation, intellectual disability and cardiac diseases. CONCLUSION: ACF is a facial dysmorphism frequently accompanied by other systemic deformities. It is a genetic abnormality that may associate with terminal 10q26.12 deletion. Early cardiac, audiologic, cranial examinations and genetic detection are needed to guide early diagnosis and treatment strategy.

Variation of Neonatal Outcomes and Care Practices for Preterm Infants <34 Weeks' Gestation in Different Regions of China: A Cohort Study.

Background: To compare outcomes and care practices of preterm infants born at <34 weeks' gestation in the different regions of China from 2015 to 2018. Methods: This cohort study enrolled all infants born at <34 weeks and admitted to 25 tertiary neonatal intensive care units across China from May 1st, 2015, to April 30th, 2018. The participating hospitals were categorized into three groups according to their distinct geographic locations: eastern China, central China, and western China. Multilevel mixed-effects logistic regression models were used to assess the independent association between neonatal outcomes and regions. Results: A total of 27,532 infants at <34 weeks' gestation were enrolled in our study. Overall, 14,178 (51.5%) infants were from 12 hospitals in eastern China, 8,069 (29.3%) from 9 hospitals in central China, and 5,285 (19.2%) from 4 hospitals in western China. Infants in eastern China had the lowest rates of mortality or any morbidity (23.3%), overall mortality (7.6%), in-hospital mortality (3.7%), and discharge against medical advice (DAMA, 6.3%), compared with central (27.8, 11.3, 5.0, and 10.6%, respectively) and western China (37.4, 19.4, 7.7, and 19.4%, respectively). Multilevel mixed-effects logistic regression showed that infants in western China were exposed to the highest risks of mortality or any morbidity, overall mortality, in-hospital mortality, and DAMA. Significant variations of care practices existed in three regions. Infants in central China had the longest duration of the first course of invasive ventilation, the lowest rate of continuous positive airway pressure within 24 h after birth, the lowest rate of breast milk feeding, the latest initiation of feeds, and the longest duration of total parenteral nutrition among the three regions. Conclusions: We identified marked disparities in outcomes and clinical care practices of preterm infants born at <34 weeks' gestation in different regions of China. Targeted quality improvement efforts are needed to improve the outcomes of premature infants in different regions of China.

Causes of severe neonatal hyperbilirubinemia: a multicenter study of three regions in China.

BACKGROUND: Available evidence suggests that our country bear great burden of severe hyperbilirubinemia. However, the causes have not been explored recently in different regions of China to guide necessary clinical and public health interventions. METHODS: This was a prospective, observational study conducted from March 1, 2018, to February 28, 2019. Four hospitals in three regions of China participated in the survey. Data from infants with a gestational age ≥ 35 weeks, birth weight ≥ 2000 g, and total serum bilirubin (TSB) level ≥ 17 mg/dL (342 µmol/L) were prospectively collected. RESULTS: A total of 783 cases were reported. Causes were identified in 259 cases. The major causes were ABO incompatibility (n = 101), glucose-6-phosphate dehydrogenase deficiency (n = 76), and intracranial hemorrhage (n = 70). All infants with glucose-6-phosphate dehydrogenase deficiency were from the central south region. Those from the central south region had much higher peak total bilirubin levels [mean, 404 µmol/L; standard deviation (SD), 75 µmol/L] than those from the other regions (mean, 373 µmol/L; SD, 35 µmol/L) (P < 0.001). CONCLUSIONS: ABO incompatibility was the leading cause in the east and northwest regions, but cases in the central south region were mainly caused by both ABO incompatibility and glucose-6-phosphate dehydrogenase deficiency, and infants in this region had a much higher peak total bilirubin level. Intracranial hemorrhage may be another common cause. More thorough assessments and rigorous bilirubin follow-up strategies are needed in the central south region.

Genome-wide and interaction linkage scan for nonsyndromic cleft lip with or without cleft palate in two multiplex families in Shenyang, China.

OBJECTIVES: To identify the loci involved in nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Northern Chinese people in Shenyang by using genomewide and interaction linkage scan. METHODS: Two multiplex families in Shenyang from North China were ascertained through probands with NSCL/P. Blood of every member was drawn for DNA extraction and analysis. Genotypes were available for 382 autosomal short tandem repeat (STR) markers from the ABI Prism Linkage Mapping Set version 2.5. Linkage between markers and NSCL/P was assessed by 2-point parametric LOD scores, multipoint-heterogeneity parametric LOD scores (HLODs), and multipoint nonparametric linkage score (NPL). RESULTS: The initial scan suggested linkage on Chromosomes 1, 2, and 15. In subsequent fine mapping, 1q32-q42 showed a maximum multipoint LOD score of 1.9(empirical P=0.013) and an NPL score of 2.35 (empirical P=0.053). For 2p24-p25, the multipoint NPL increased to 2.94 (empirical P=0.007). 2-locus interaction analysis obtained a maximum NPL score of 3.73 (P=0.00078) and a maximum LOD score of 3 for Chromosome 1 (at 221 cM) and Chromosome 2 (at 29 cM). CONCLUSION: Both parametric and nonparametric linkage scores greatly increased over the initial linkage scores on 1q32-q42, suggesting a susceptibility locus in this region. Nonparametric linkage gave a strong evidence for a candidate region on chromosome 2p24-p25. The superiority of 2-locus linkage scores compared to single-locus scores gave additional evidence for linkage on 1q32-q42 and 2p24-p25, and suggested that certain genes in the two regions may contribute to NCSL/P risks with interaction.

Magnetic compression anastomosis for rectal atresia following necrotizing enterocolitis: A case report.

RATIONALE: Rectal atresia caused by necrotizing enterocolitis (NEC) is a serious and rare complication in children. Magnetic compression anastomosis (MCA) has been effectively applied in children with congenital oesophageal atresia and biliary atresia. Herein, we reported a case of successfully application of MCA in an infant with rectal atresia following NEC. PATIENT CONCERNS: A 30 weeks premature birth female fetal infant was transferred to our neonatal intensive care unit due to premature delivery, low birth weight, and neonatal respiratory distress. On postpartum day 11, the infant developed abdominal distension and mucosanguineous feces. This infant was then clinically diagnosed as NEC. She underwent anesthesia and intestinal fistula operation on postpartum day 11 because of NEC. DIAGNOSIS: After 3 months, radiographic examination revealed rectal atresia and stricture. INTERVENTIONS: This infant was successfully treated with MCA following a cecum-rectal anastomosis and ileocecal valve was reserved. OUTCOMES: On postoperative day 9, she passed the 2 magnets per rectum. In addition, there were no difficult defecation or fecal incontinence or other short-term complications. After the 7-month follow-up, the patient had an excellent clinical outcome. LESSONS: MCA is a feasible and effective method for treating rectal atresia in infants.

Magnetic compression for anastomosis in treating an infant born with long-gap oesophageal atresia: A case report.

RATIONALE: Neonatal long-gap esophageal atresia (LGEA) with tracheoesophageal fistula (TEF) is an uncommon but serious congenital malformation of the esophagus in newborns, and it remains challenging for pediatric surgeons. Magnetic compress has been shown to be effective for the treatment of LGEA in children and adults. However, the implementation of this unique technique for neonatal LGEA has not been evaluated. PATIENT CONCERNS: A female infant was born at 37 weeks of gestation. Prenatal ultrasound imaging revealed signs of esophageal atresia, including the absence of the gastric bubble and polyhydramnios. DIAGNOSES: A diagnosis of LGEA with TEF was confirmed at birth by contrast X-ray. INTERVENTIONS: She was treated with magnetic compression anastomosis (MCA) following an esophago-esophagostomy. Two magnetic rings were customized, and the MCA was conducted during the same stage surgery of ligating the TEF. Under the magnetic force, the 2 magnet rings pulled along the gastric tube to achieve anastomosis. The postoperative permanent suction of these 2 pouches was instituted, and spontaneous growth was awaited. Magnet removal was performed at 36 days, and enteral nutrition was continued via a gastric tube for 4 weeks at post-operation. OUTCOMES: The upper gastrointestinal contrast confirmed the anastomotic patency perfectly after 3 months. The patient was followed up for 18 months, and exhibited durable esophageal patency without dysphagia. LESSONS: These results suggest that MCA is feasible and effective for treating LGEA in infants.

[No association of the A2756G polymorphism of methionine synthase gene with nonsyndromic cleft lip with or without cleft palate].

OBJECTIVE: To study the association of the A2756G polymorphism of the methionine synthase (MS) gene with nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Chinese. METHODS: Ninety-seven NSCL/P case-parent triads were selected as the case group. One hundred and four healthy subjects and their biological parents were selected as control group. For all subjects the A2756G polymorphism of the MS gene was examined by PCR-RFLP method. RESULTS: There was no statistical difference in genotype and allele frequencies for MS A2756G variants among family members between case group and control group. The GG genotype was not detected in the offsprings and mothers. The odds ratio and confidence interval of genotype AG in offspring, father and mother were 1.78(0.74-4.34), 0.80(0.36-1.79) and 1.26(0.54-2.93) respectively. The odds ratio and confidence interval of allele G in offspring, father and mother were 1.70(0.78-3.73), 0.88(0.49-1.75), and 1.23(0.59-2.60) respectively. The G allele did not increase the risk of NSCL/P. Transmission disequilibrium test (TDT) analysis yielded no evidence of linkage disequilibrium (chi-square=0.034,P>0.05). The results of haplotype-based haplotype relative risk (HHRR) analysis (chi-square=0.03,P>0.05) and family-based association tests (FBAT) (Z=0.186, P>0.05) failed to show association between the MS A2756G variant and the risk of NSCL/P. CONCLUSION: The A2756G polymorphism of the MS gene was not associated with NSCL/P in Chinese in the present study.